Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19][CH2:18]1>C(#N)C>[CH:9]1([NH:8][C:6](=[O:7])[C:5]2[CH:12]=[CH:13][C:2]([N:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:22]3)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:11][CH2:10]1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: O=C(NC1CC1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC#N
Product: O=C(NC1CC1)c1ccc(N2CCC(CCN3CCCCC3)CC2)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
A mixture of 0.612 g (2.51 mmol) of 4-chloro-N-cyclopropyl-3-nitro-benzamide and 0.50 g (2.5 mmol) of 1-(2-piperidin-4-yl-ethyl)-piperidine in acetonitrile (0.5 mL) are heated at 110° C. for 30 minutes in a microwave reactor. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.80 g (79%) of N-cyclopropyl-3-nitro-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide.
Reaction SMILES: [F:1][C:2]1C=[CH:8][C:7]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH3:22])[C:14](=[O:23])[NH:13][N:12]=2)=[CH:6][C:3]=1C#N.[OH-:24].[K+].[CH2:26]([OH:28])[CH3:27]>O>[F:1][C:2]1[CH:3]=[CH:6][C:7]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH3:22])[C:14](=[O:23])[NH:13][N:12]=2)=[CH:8][C:27]=1[C:26]([OH:24])=[O:28]
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C#N)c3)c12
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Temperature: 100 °C
Yield: 83 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzonitrile (124) (2.7 g, 8.73 mmol) and potassium hydroxide (4.90 g, 87.30 mmol) were added to ethanol (20 mL) and water (50 mL) and heated at 100° C. for 5 hours. The ethanol was evaporated off and the aqueous was extracted with ethyl acetate (1×75 mL). The aqueous was then acidified to pH1 with conc HCl to afford a solid, this was filtered, washed with water and dried to afford the desired material as a white solid (2.370 g, 83%); 1H NMR (400.132 MHz, DMSO) δ 3.82 (3H, s), 4.40 (2H, s), 7.16-7.23 (1H, m), 7.40-7.46 (2H, m), 7.64-7.68 (1H, m), 7.76 (1H, t), 7.84-7.88 (1H, m), 12.96-13.28 (1H, m), 12.59-12.63 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH2:50]>CN(C=O)C>[O:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH2:41][CH:40]1[CH2:49][NH:50][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: NCC1COc2ccccc2O1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
5-methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of TBF to remove a by-product and to give 1.8 g (74%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-1H-indole-3-yl)-butanamide, as an oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[C:10]([F:16])=[N:11][CH:12]=[CH:13][C:14]=1I)[CH:7]=[CH2:8].[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21].O>CCCCCC.C1COCC1>[CH2:6]([C:9]1[C:10]([F:16])=[N:11][CH:12]=[CH:13][C:14]=1[C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])[CH:7]=[CH2:8]
Reactant: CCC(=O)CC
Reactant: C=CCc1c(I)ccnc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1c(C(O)(CC)CC)ccnc1F
Temperature: -75 °C
Reaction time: 6 h

Procedure:
27 ml (43.3 mmol) of 1.6M butyllithium in hexane are added, at −75° C., to a solution of 11.4 g (43.3 mmol) of 3-allyl-2-fluoro-4-iodopyridine (prepared according to the process described in J.O.C., 1993, 58, pp.7832) in 250 ml of THF. After 30 minutes' stirring at −75° C. a solution of 4.6 ml of 3-pentanone in 100 ml of THF is added dropwise. The reaction mixture is stirred for 6 hours at −75° C. After returning to room temperature, the mixture is hydrolysed with 100 ml of water and extracted with ethyl acetate. The organic phase is dried, concentrated and purified by chromatography over silica (eluant:cyclohexane/ethyl acetate 8/2) to yield the expected product.
Reaction SMILES: [CH2:1]([N:4]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[NH:30])=[CH:25][CH:24]=3)[CH2:13][C@:14]([CH2:16][C:17]([OH:19])=O)([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:46]([O:45][C:43](=[O:44])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[NH:30])=[CH:27][CH:28]=3)[CH2:13][C@@:14]([CH3:15])([CH2:16][C:17](=[O:19])[NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:8]2=[N:7][CH:6]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)O
Reactant: Nc1ccccc1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)Nc1ccccc1
Yield: 56.6 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18 g, intermediate 39a (20 mg, 0.028 mmol) was coupled with aniline (3.39 mg, 0.036 mmol) to provide 12.4 mg (57%) of intermediate 40a. MS (ESI) 782.3 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH:4]([S:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9](N)[C:10](=[O:12])[CH3:11].[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=C(C(O)=O)[CH:29]=1>>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([CH:4]([C:3](=[O:27])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:11]2[CH:29]=[N:28][C:37]3[C:32]([CH:31]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:12])=[O:15])=[CH:17][CH:18]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)C(CCCCN(N)C(C)=O)C(=O)NO)cc1
Reactant: O=C(O)c1cnc2ccccc2c1
Product: CC#CCOc1ccc(S(=O)C(CCCCNC(=O)c2cnc3ccccc3c2)C(=O)NO)cc1

Procedure:
6-(Amino-acetylamino)-2-(4-but-2-ynoxy-benzenesulfinyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 3-quinolinecarboxylic acid (1.2 g, 4.0 eq) according to the procedure in Example 13, Step E to give quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide resin.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:24])=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(Br)nc(C(=O)Cl)c1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) in one portion. After gas evolution had ceased (about 45 min.), the now homogeneous solution was stirred an additional 15 min., then the solvent was evaporated. 1,2-dichloroethane (30 mL) was added and again the solvent was evaporated to give a quantitative yield of 3 as a nearly colorless oil. This material was dissolved in CH2Cl2 (10 mL) or THF (10 mL) and used directly in subsequent coupling reactions.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH3:36][C:37]([CH3:39])=[O:38]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([C:37]([OH:38])([CH3:39])[CH3:36])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C(C)(C)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (45 mL) stirring at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (5.0 g, 21 mmol) in THF (40 mL). The resulting golden mixture was warmed to −28° C. to −23° C. (CCl4/dry ice) and stirred for 30 min. The reaction solution was cooled down to −78° C. and anhydrous acetone (1.8 mL, 25 mmol) was added. After the addition, the reaction mixture was kept in a CCl4/dry ice bath and allowed to warm to room temperature overnight. The dark solution was quenched with saturated NH4Cl and extracted with ether three times. The combined extracts were dried, filtered, concentrated. The crude residue was purified by flash column chromatography (EtOAc/Hexane) to yield the desired product (1.4 g, 22.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:5]([C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(C=Cc1cccc(Cl)c1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1cccc(Cl)c1
Yield: 73 %

Procedure:
Upon heating a solution of 24.3 g of 3-chlorobenzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 4 hours, 2-amino-6-phenyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 161°C is obtained. Yield: 73 percent of theory.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]2[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=12>CN1CCCC1=O>[CH2:1]([O:8][C:16]1[N:17]=[N:18][CH:19]=[C:20]2[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1c([N+](=O)[O-])c2cnnc(Cl)c2n1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c([N+](=O)[O-])c2cnnc(OCc3ccccc3)c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.3 ml (177 mmol) of benzyl alcohol are added dropwise at room temperature to a solution of 33.0 g (295 mmol) of potassium tert-butoxide and 1.5 g (5.9 mmol) of [18]crown-6 in 180 ml of anhydrous N-methylpyrrolidone. The mixture is subsequently stirred at room temperature for a further 1 h. A solution of 15.9 g (59 mmol) of 7-chloro-1-isobutyl-2-methyl-3-nitropyrrolo[2,3-d]pyridazine in 50 ml of anhydrous N-methylpyrrolidone is then added dropwise in the course of 15 min. The suspension is then stirred at 80° C. for 2 h. After cooling to room temperature, it is treated with 400 ml of ice-water, and extracted with 3×300 ml of ethyl acetate. The organic extracts are washed with 3×200 ml of water and subsequently dried over magnesium sulfate. The residue which remains after concentration is chromatographed on silica gel (eluent: toluene/ethyl acetate=4:1). After concentration of the fractions of Rf=0.25 and crystallization from diisopropyl ether/ethyl acetate, 5.1 g (25%) of the title compound are isolated. M.p.: 162°-164° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 29.1 %

Procedure:
After a mixture of (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-bromophenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.10 g, 0.23 mmol), 3-thiophene-boronic acid (0.045 g, 0.35 mmol), tripotassium phosphate (0.148 g, 0.7 mmol), 1,2-dimethoxyethane (3 mL) and water (3 mL) was placed in a flask under nitrogen, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.019 g, 0.023 mmol) was added to the mixture, and the resulting mixture was stirred at reflux for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with dichloromethane (50 mL). The extract was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform). The resulting compound was triturated with ethyl acetate/n-hexane to give (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.029 g, yield: 29%) as pale brown powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O)=O)C.C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C1(C)C(C)=CC=CC=1>[NH2:23][C:22]1[NH:24][C:4](=[O:3])[C:6]2[CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[N:21]=1
Reactant: CCOC(=O)C1CCc2ccccc2C1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1C
Product: Nc1nc2c(c(=O)[nH]1)CCc1ccccc1-2
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 2-ethoxycarbonyl-1-tetralone (0.65 g) and guanidine carbonate (0.65 g) in xylene (15 ml) was refluxed overnight and, after cooling to room temperature, the tan solid was collected by filtration, washed with water and alcohol, and then dried to yield 0.24 g of tan solid, m.p.>300° C. The solid was dissolved in Con.-HCl, concentrated in vacuo to dryness, and recrystallized from ethanol to yield a colorless solid product, (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([CH:22]([CH3:24])[CH3:23])(C(OCC)=O)[C:12]([O:14]CC)=[O:13])[N:4]=1.[OH-].[Na+].O>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:22]([CH3:24])[CH3:23])[C:12]([OH:14])=[O:13])[N:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)(c1nc(OC)cc(OC)n1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(C(C(=O)O)C(C)C)n1
Yield: 75.1 %

Procedure:
10 g of diethyl 2-(4,6-dimethoxypyrimidin-2-yl)-2-isopropylmalonate, 5,0 g of sodium hydroxide, 20 ml of water and 50 ml of methanol were placed in a round bottom flask, and were stirred under heat-refluxing for 6 hours. The reaction liquor was concentrated, and 100 ml of water was added thereto. The reaction liquor was adjusted to a pH of from 3 to 4 with a dilute hydrochloric acid under cooling with ice, and was extracted twice with 100 ml of diethyl ether. The extracted liquor was washed with water, and was dried with anhydrous sodium sulfate for one night. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure to obtain 5.8 g of a crude crystal. The crude crystal thus obtained was recrystallized from ether-hexane to obtain 5.3 g of the aimed product of white powder (yield=75.1%) having a melting point of 99°-101° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:32][C:29]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27][N:26]([C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccccc1OCc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2OCc2ccccc2)CC1
Yield: 59 %

Procedure:
2-Benzyloxybromobenzene (242.3 g) was reacted with 1-benzyloxycarbonyl-4-piperidone (214.7 g) according to the method described for Example 2e to afford 4-hydroxy-4-(2-benzyloxyphenyl)-N-Cbz-piperidine (226.75 g) after extraction and chromatography using 10-30% ethyl acetate in hexanes. 1H NMR (300 MHz, CDCl3) δ 7.40-7.21 (m, 12H), 6.98 (m, 2H), 5.12 (s, 4H), 4.11 (br s, 3H), 3.35 (br s, 2H), 2.03 (br s, 4H). A sample of this material (235 g) was reacted with triethylsilane (405 mL) and trifluoroacetic acid (195 mL) according to the method described for Example 2f. Following extraction and chromatography (10-25% ethyl acetate in hexane), residual triethylsilane was removed by distillation (50-60° C., 800-900 millitorr) to afford 4-(2-benzyloxyphenyl)-N-Cbz-piperidine (179.3 g). A solution of this material (4.01 g) in ethanol (60 mL) was shaken for 24 h with palladium hydroxide on carbon [Pearlman's catalyst] (2.2 g) under hydrogen (50 psi). The catalyst was removed by filtration, the filtrate was concentrated and triturated with acetone to afford 4-(2-hydroxyphenyl)-piperidine (0.75 g) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.02 (m, 2H), 6.82 (d, 1H), 6.72 (t, 1H), 3.20 (br d, 2H), 3.02 (m, 1H), 2.85 (tt, 2H), 1.74 (m, 4H). Using standard reductive amination conditions N-[2-(S)-(3,4-dichlorophenyl)]-4-oxobutyl-N-methyl-3-cyano-1-naphthamide (0.213 g) was reacted with 4-(2-hydroxyphenyl)-piperidine to afford N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[2-hydroxyphenyl]-1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37](O)[CH2:38][CH2:39][CH:40]=C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:40][CH2:39][CH:38]=[CH2:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: C=CCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 99.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-penten-1-ol (20 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (67 mg, yield 95%).
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[C:14]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH:20]1O)[CH2:26]2)(=[O:17])[CH:15]=[CH2:16].N(C(C)(C)C(OC)=O)=NC(C)(C)C(OC)=[O:34].Cl>CC(O)C.CCCCCCC.CO>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[C:14]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:34])([CH2:22]3)[CH2:20]1)[CH2:26]2)(=[O:17])[CH:15]=[CH2:16]
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Reactant: C=CC(=O)OC12CC3CC(CC(C3)C1O)C2
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Solvent: CC(C)O
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Product: C=Cc1ccc(O)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Into a flask was charged 92.8 g (0.53 mol) of 4-tert-butoxystyrene, 13.0 g (0.06 mol) of 3 hydroxy-1-adamantyl acrylate, 52.9 g of methanol and 105.8 g of 2-propanol, and they were refluxed under a nitrogen atmosphere at 75° C. Separately, 6.1 g of dimethyl 2,2′-azobis(2-methylpropionate) was dissolved in 17.6 g of 2-propanol to prepare a solution which was dropped into the above-mentioned monomer solution kept at 75° C. over 30 minutes, then, the resulted mixture was refluxed itself for 8 hours. To this was further added 193.9 g of 2-propanol, and the resulted mixture was refluxed again at 75° C. Into this solution was dropped a mixed solution of 18.3 g of 36% hydrochloric acid and 18.3 g of 2-propanol. Subsequently, the mixture was refluxed for 4 hours at the same temperature to cause hydrolysis, then, the solution was cooled to room temperature. To this reaction mass was added 528.9 g of n-heptane, and the lower resin layer was removed. This resin layer was dissolved in 52.9 g of acetone, and 528.9 g of n-heptane was added, and the lower resin layer was removed again. The resulted resin layer was dissolved in 634.7 g of methyl isobutyl ketone, and 211.6 g of ion exchanged water was added to this and the mixture was stirred and allowed to stand still, then, the organic layer part was removed. Further, an operation of addition of 211.6 g of ion exchanged water, stirring and separation was repeated four times. This organic layer was distilled under reduced pressure until the solution amount after distillation was 230.8 g under conditions of a temperature of 60° C. and a pressure of 80 Torr or less, and dehydrated azeotropically, to obtain a methyl isobutyl ketone solution of a copolymer of 4-hydroxystyrene and 3-hydroxy-1-adamantyl acrylate. The solid concentration of the resulted resin solution was 26.3%, and this copolymer had a weight-average molecular weight of 11400 and a polydispersity of 1.77.